A serine-conjugated butyrate prodrug with high oral bioavailability suppresses autoimmune arthritis and neuroinflammation in mice

被引:18
作者
Cao, Shijie [1 ,2 ]
Budina, Erica [1 ]
Raczy, Michal M. [1 ]
Solanki, Ani [1 ,3 ]
Nguyen, Mindy [1 ,3 ]
Beckman, Taryn N. [1 ]
Reda, Joseph W. [1 ]
Hultgren, Kevin [1 ]
Ang, Phillip S. [1 ]
Slezak, Anna J. [1 ]
Hesser, Lauren A. [1 ]
Alpar, Aaron T. [1 ]
Refvik, Kirsten C. [1 ]
Shores, Lucas S. [1 ]
Pillai, Ishita [1 ]
Wallace, Rachel P. [1 ]
Dhar, Arjun [1 ]
Watkins, Elyse A. [1 ]
Hubbell, Jeffrey A. [1 ,4 ,5 ]
机构
[1] Univ Chicago, Pritzker Sch Mol Engn, Chicago, IL 60637 USA
[2] Univ Washington, Sch Pharm, Dept Pharmaceut, Seattle, WA 98195 USA
[3] Univ Chicago, Anim Resource Ctr, Chicago, IL USA
[4] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA
[5] Univ Chicago, Comm Canc Biol, Chicago, IL 60637 USA
关键词
CHAIN FATTY-ACIDS; DISTAL ULCERATIVE-COLITIS; BLOOD-BRAIN-BARRIER; T-CELL RESPONSES; MULTIPLE-SCLEROSIS; METABOLITE BUTYRATE; INTESTINAL BARRIER; RECTAL IRRIGATION; ENERGY-METABOLISM; DENDRITIC CELLS;
D O I
10.1038/s41551-024-01190-x
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
Butyrate-a metabolite produced by commensal bacteria-has been extensively studied for its immunomodulatory effects on immune cells, including regulatory T cells, macrophages and dendritic cells. However, the development of butyrate as a drug has been hindered by butyrate's poor oral bioavailability, owing to its rapid metabolism in the gut, its low potency (hence, necessitating high dosing), and its foul smell and taste. Here we report that the oral bioavailability of butyrate can be increased by esterifying it to serine, an amino acid transporter that aids the escape of the resulting odourless and tasteless prodrug (O-butyryl-l-serine, which we named SerBut) from the gut, enhancing its systemic uptake. In mice with collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of multiple sclerosis), we show that SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. SerBut may become a promising therapeutic for autoimmune and inflammatory diseases. The esterification of butyrate to serine makes for an odourless and tasteless oral prodrug that ameliorated disease severity and reduced inflammatory responses in mouse models of rheumatoid arthritis and multiple sclerosis.
引用
收藏
页码:611 / 627
页数:25
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